BHD Research Blog

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BHD Research Blog is the official blog of, the primary online resource for anyone interested in Birt-Hogg-Dubé Syndrome, a rare genetic condition linked to benign skin growths, collapsed lung and kidney cancers. In the BHD Research Blog, we focus on analysing current research in BHD and related fields, as well as considering wider issues relating to rare diseases.

Joana Guedes
242 posts

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  • October 21, 2016
  • 05:39 AM

Chest CT in patients with spontaneous pneumothorax is cost-effective

by Joana Guedes in BHD Research Blog

Patients that present with a spontaneous pneumothorax (SP) without a known medical history of lung disease are usually diagnosed as primary spontaneous pneumothorax - a pneumothorax that occurs without underlying diseases. However, underlying diffuse cystic lung diseases such as Birt-Hogg-Dube syndrome (BHD), lymphangioleiomyomatosis (LAM) and pulmonary Langerhans cell histiocytosis (PLCH) may have a spontaneous pneumothorax as their first symptom. In their new study, Gupta et al. (2016) evaluat........ Read more »

  • September 30, 2016
  • 06:12 AM

BHD at the International Rare Lung Diseases Research Conference 2016

by Joana Guedes in BHD Research Blog

The International Rare Lung Diseases Research Conference (RLDC) and LAM symposium were held last week over four days. They brought together clinicians, scientists, patients and families to Cincinnati to review research developments in rare lung disease and to promote dialogue between the research community and patients. Next week’s blog will focus on the highlights of the entire conference. This week the blog is focused on the BHD syndrome specific talk and poster.... Read more »

Toro JR, Pautler SE, Stewart L, Glenn GM, Weinreich M, Toure O, Wei MH, Schmidt LS, Davis L, Zbar B.... (2007) Lung cysts, spontaneous pneumothorax, and genetic associations in 89 families with Birt-Hogg-Dubé syndrome. American journal of respiratory and critical care medicine, 175(10), 1044-53. PMID: 17322109  

  • September 23, 2016
  • 04:14 PM

PD-L1 expression associates with non-inactivated VHL ccRCC

by Joana Guedes in BHD Research Blog

The loss of the of the tumor suppressor gene VHL and the subsequent deregulation of VHL/HIF/VEGF signalling are known to play a role in development of clear cell renal cell carcinoma (ccRCC). Renal tumours associated with BHD syndrome are histologically diverse and include a percentage of ccRCC (Pavlovich et al., 2002). Anti-angiogenic therapies targeting the VHL/HIF/VEGF pathway have emerged in past years (Rini et al., 2006) but the development of resistance to these therapeutic agents is leadi........ Read more »

  • September 16, 2016
  • 05:01 AM

Air travel and diving possibly increase risk of pneumothorax in BHD patients

by Joana Guedes in BHD Research Blog

Birt–Hogg–Dubé syndrome is caused by germline mutations in the FLCN gene and characterized by skin fibrofolliculomas, lung cysts, spontaneous pneumothorax (SP) and renal cancer. Because sudden changes in air pressure can increase the chances of developing a collapsed lung, a concern many BHD patients have is whether it is safe to air travel and scuba dive, or whether this increases the chances of a pneumothorax. In a new study, Johannesma et al. (2016) evaluate the incidence ........ Read more »

Johannesma, P., van de Beek, I., van der Wel, J., Paul, M., Houweling, A., Jonker, M., van Waesberghe, J., Reinhard, R., Starink, T., van Moorselaar, R.... (2016) Risk of spontaneous pneumothorax due to air travel and diving in patients with Birt–Hogg–Dubé syndrome. SpringerPlus, 5(1). DOI: 10.1186/s40064-016-3009-4  

  • September 9, 2016
  • 10:24 AM

C9orf72-SMCR8 complex, analogous to FLCN- FNIP, localizes to lysosomes and regulates mTORC1

by Joana Guedes in BHD Research Blog

The DENN protein module contains a longin domain, a DENN domain and a d-DENN domain. Nookala et al. (2012) identified a DENN module in folliculin (FLCN), the Birt-Hogg-Dube tumour suppressor. The DENN module is believed to be a GEF for Rab-GTPases, although FLCN is believed to act as a GAP for RagC (Tsun et al., 2013) as is its yeast homologue, LST7, in interaction with the yeast FNIP homologue Lst4 (Pacitto et al., 2015). A recent bioinformatic study identified DENN domains in several other ........ Read more »

  • September 2, 2016
  • 07:28 AM

Mitochondrial function during muscle fiber type transition by a miR‐499/Fnip1/AMPK circuit

by Joana Guedes in BHD Research Blog

Contractile fiber type and mitochondrial function are two key factors of skeletal muscle function. However, the exact mechanism for coupling the two remains unknown. The genes encoding type I myosins Myh7/Myh7b regulate muscle fiber type switching by encoding their intronic miRNAs, miR-208b and miR-499. In a new study, Liu et al., 2016 use transgenic mice to show that miR-499 directly targets the gene encoding folliculin‐interacting protein‐1 (Fnip1), which negatively regulates AMPK. AMPK ........ Read more »

  • August 26, 2016
  • 05:03 AM

A new Birt-Hogg-Dubé Syndrome review

by Joana Guedes in BHD Research Blog

Gupta et al. (2016b) recently published a review about Birt-Hogg-Dubé Syndrome (BHD) exploring the key points and research advances in genetics and pathogenesis, clinical manifestations, diagnosis and disease management.... Read more »

Gupta N, Sunwoo BY, & Kotloff RM. (2016) Birt-Hogg-Dubé Syndrome. Clinics in chest medicine, 37(3), 475-86. PMID: 27514594  

  • August 12, 2016
  • 05:10 AM

Simulation study suggests that mutations induce conformational changes in FLCN - possible cause of Birt-Hogg-Dubé syndrome

by Joana Guedes in BHD Research Blog

Germline mutations of the folliculin gene are normally responsible for Birt–Hogg–Dubé (BHD) syndrome. The 3D structure of the C-terminal domain of folliculin (FLCN), folliculin-CT, has been previously determined (Nookala et al., 2012). FLCN is a tumor suppressor and a guanine nucleotide exchange factor (GEF) for Rab35. GEF activity of FLCN towards its GTPase might be essential for cellular processes. Most of the reported FLCN mutations lead to the BHD phenotype (Lim et al., 20........ Read more »

  • August 5, 2016
  • 05:09 AM

Multiple germline mutations in rare inherited cancer syndrome genes

by Joana Guedes in BHD Research Blog

A recent study by Whitworth et al. (2016) reports five new cases of multiple germline mutations in inherited cancer syndrome genes, three of them involve the combination of mutations in FLCN with NF1, TP53, and MSH2, respectively.... Read more »

Whitworth J, Skytte AB, Sunde L, Lim DH, Arends MJ, Happerfield L, Frayling IM, van Minkelen R, Woodward ER, Tischkowitz MD.... (2016) Multilocus Inherited Neoplasia Alleles Syndrome: A Case Series and Review. JAMA oncology, 2(3), 373-9. PMID: 26659639  

  • July 22, 2016
  • 09:01 AM

Update on clinical trials and treatments for RCC

by Joana Guedes in BHD Research Blog

Renal cell carcinoma (RCC) is the most common type of kidney cancer and although the majority of cases are sporadic approximately 3% of cases are caused by genetic conditions such as BHD, VHL, HLRCC and TSC (Randall et al., 2014). These inherited forms of RCC have provided great insights into sporadic cancer genetics. BHD patients can develop multiple kidney tumours. In most cases these tumours are small local RCCs that can be surgically removed. However, these treatments are not without risk,........ Read more »

  • July 14, 2016
  • 10:14 AM

Folliculin is required for embryonic brain development in zebrafish

by Joana Guedes in BHD Research Blog

Birt-Hogg-Dubé syndrome (BHD) is caused by mutations in the gene encoding folliculin (FLCN). How this leads to the BHD clinical manifestations is not yet clear. Since homozygous mutations of FLCN are lethal in mice, rats and dogs at early embryonic stage (Hasumi et al., 2009), zebrafish is a valuable alternative model to study the developmental functions of FLCN. Newly published research from Kenyon et al. (2016) examines the role of FLCN in zebrafish development using morpholino oligonuc........ Read more »

Kenyon EJ, Luijten MN, Gill H, Li N, Rawlings M, Bull JC, Hadzhiev Y, van Steensel MA, Maher E, & Mueller F. (2016) Expression and knockdown of zebrafish folliculin suggests requirement for embryonic brain morphogenesis. BMC developmental biology, 16(1), 23. PMID: 27391801  

  • July 8, 2016
  • 12:38 PM

FNIP1 and FNIP2 inhibit Hsp90 chaperone cycle and enhance drug binding

by Joana Guedes in BHD Research Blog

Heat shock protein-90 (Hsp90) is a molecular chaperone required for folding, stability and activity of many proteins, known as clients, including drivers of tumour initiation, progression and metastasis (Rohl et al. 2013). ATPase binding and hydrolysis is essential for the chaperone function of Hsp90. ATPase function is regulated by other proteins known as co-chaperones. In an interesting new study, Woodford et al. (2016) show that the stability of the tumour suppressor folliculin (FLCN), whose ........ Read more »

Woodford MR, Dunn DM, Blanden AR, Capriotti D, Loiselle D, Prodromou C, Panaretou B, Hughes PF, Smith A, Ackerman W.... (2016) The FNIP co-chaperones decelerate the Hsp90 chaperone cycle and enhance drug binding. Nature communications, 12037. PMID: 27353360  

  • June 17, 2016
  • 05:49 AM

FLCN activates mTORC1 by maintaining lysosomal leucine level

by Joana Guedes in BHD Research Blog

The intracellular amino acid pool within the lysosome has been shown to activate the mTORC1 signaling pathway (Zoncu et al., 2011; Jewell et al., 2013). However, how the sequester of the signaling molecules within the lysosome occurs remains poorly understood. New research from Wu et al. (2016) shows that the suppression of FLCN, a tumour suppressor gene associated with the Birt-Hogg-Dubé (BHD) syndrome, controls mTORC1 activity by modulating the lysosomal leucine levels. FLCN exerts this new f........ Read more »

  • June 10, 2016
  • 06:14 AM

BHD syndrome and thyroid conditions

by Joana Guedes in BHD Research Blog

Dong et al., (2016) have recently reported two BHD syndrome patients also affected with papillary thyroid cancer. Lesions were bilateral and multifocal and small lymph node metastases occurred. Due to the small number of patients in the study the authors are unsure whether thyroid cancer in BHD patients is susceptible to exhibiting bilaterally and lymph node metastasis. However, they suggest considering thyroidectomy and prophylactic lymph node dissection for thyroid cancer patients with BHD. Th........ Read more »

  • June 3, 2016
  • 11:43 AM

Anonymising and sharing patient data

by Joana Guedes in BHD Research Blog

Patient data is extremely valuable for biomedical and healthcare research. Collecting and sharing patient data globally can lead to several benefits such as better understanding diseases, identifying patterns in public health and disease, developing and monotoring drugs and treatments, allowing researchers to build on the work of others efficiently and finding suitable candidates to take part in clinical trials. However, concerns about privacy have been a barrier for making patient data availabl........ Read more »

El Emam K, Rodgers S, & Malin B. (2015) Anonymising and sharing individual patient data. BMJ (Clinical research ed.). PMID: 25794882  

  • May 27, 2016
  • 12:33 PM

Starvation-induced FLCN association with lysosomes via a Rab34–RILP complex

by Joana Guedes in BHD Research Blog

Dynamic positioning of lysosomes in the cytoplasm plays an important role in their function and is, in part, regulated by cellular nutrient status. The FLCN/FNIP complex is known to be active on the lysosome surface, where it interacts with Rag GTPases, supports the nutrient‐dependent recruitment and activation of mTORC1, and regulates the localisation of lysosome associated transcription factors (Petit et al., 2013; Tsun et al., 2013). New research from Starling et al. (2016) now shows that f........ Read more »

  • February 26, 2016
  • 04:50 AM

BHD pulmonary cysts: The stretch hypothesis

by Joana Guedes in BHD Research Blog

The majority of BHD patients develop pulmonary cysts and approximately 1 in 3 will suffer a pneumothorax. Although BHD pulmonary cysts have defining characteristics compared to other cystic lung diseases (as discussed in recent reviews), the underlying pathogenesis is not yet clearly understood. A recent review from Kennedy, Khabibullin & Henske (2016) summarises the current understanding of BHD pulmonary pathology relative to the stretch hypothesis for cyst formation.... Read more »

  • February 12, 2016
  • 04:16 AM

Maintained disomic chromosome 17 as a diagnostic marker for BHD-associated chromophobe RCC

by Joana Guedes in BHD Research Blog

Renal cell carcinomas (RCCs) can be life-threatening and although mostly sporadic, approximately 5% are associated with genetic conditions such as BHD. Early identification of families carrying cancer-predisposing mutations enables access to regular screening and earlier treatment. However, it can be difficult to distinguish between sporadic and inherited RCC based on standard immunohistological analysis. New research from Kato et al. (2016) assessed whether variability in the chromosomal status........ Read more »

  • February 5, 2016
  • 09:00 AM

TSC2 mutations confer everolimus sensitivity in hepatocellular carcinomas

by Joana Guedes in BHD Research Blog

Hepatocellular carcinomas (HCCs) are the third leading cause of cancer deaths globally; frequently diagnosed only in the advanced stages and aggressive in nature. Although enhanced mTOR activity has a key role in HCC tumourigenesis, the EVOLVE-1 clinical trial of mTOR inhibitor everolimus found no associated improvement in overall survival (Zhu et al., 2014). However, everolimus is an effective treatment for tuberous sclerosis complex (TSC) manifestations, a rare disease associated with mutation........ Read more »

  • January 29, 2016
  • 04:23 AM

A role for dermatologists in diagnosing BHD earlier

by Joana Guedes in BHD Research Blog

Birt-Hogg-Dubé (BHD) syndrome was initially described as a heritable dermatological condition based on the presence of multiple fibrofolliculomas, trichodiscomas and acrochordons in a Canadian kindred (Birt et al., 1977). Now it is known that BHD patients can also develop pulmonary cysts, with an associated risk of pneumothorax, and bilateral, multifocal renal tumours. Due to the risk of tumour development it is important that patients are diagnosed early, enabling them to access regular ........ Read more »

Tellechea O, Cardoso JC, Reis JP, Ramos L, Gameiro AR, Coutinho I, & Baptista AP. (2015) Benign follicular tumors. Anais brasileiros de dermatologia, 90(6), 780-98. PMID: 26734858  

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